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Abstract

Introduction

Diarrheal diseases are the second leading cause of childhood morbidity and mortality
in developing countries and an important cause of malnutrition. An estimated 0.75
million children below 5 years of age die from diarrhea. Vomiting associated with
acute gastroenteritis (AGE) is a distressing symptom and limits the success of oral
rehydration in AGE leading to an increased use of intravenous rehydration, prolonged
emergency department stay and hospitalization. In this review we estimate the effect
of antiemetics in gastroenteritis in children.

Methods

We conducted a systematic review of all the efficacy and effectiveness studies. We
used a standardized abstraction and grading format and performed meta-analyses for
all outcomes with more than two studies. The estimated effect of antiemetics was determined
by applying the standard Child Health Epidemiology Reference Group (CHERG) rules.

Results

We included seven studies in the review. Antiemetics significantly reduced the incidence
of vomiting and hospitalization by 54%. Antiemetics also significantly reduced the
intravenous fluid requirements by 60%, while it had a non-significant effect on the
ORT tolerance and revisit rates.

Conclusion

Antiemetics are effective for the management of gastroenteritis in children and have
the potential to decrease morbidity and mortality burden due to diarrhea, when introduced
and scaled up.

Introduction

Approximately 6.9 million deaths of children under five years occurred in 2011 due
to preventable and treatable causes [1]. Diarrheal diseases are a leading cause of childhood morbidity and mortality in developing
countries and an important cause of malnutrition. An estimated 0.751 million children
below 5 years of age die from diarrhea and 8 out of 10 of these deaths occur in the
first two years of life [2]. The incidence of diarrhea has declined from 3.4 episodes/child year in 1990 to 2.9
episodes/child year in 2010 [3] showing that improvements have been observed, but over a greater span of time.

In 1996, The American Academy of Pediatrics (AAP) issued a consensus statement that
antiemetic drugs were not recommended in children with gastroenteritis and healthcare
providers should be aware of their potential side effects [4]. However in 2003, the Centers for Disease Control (CDC) and Prevention issued a report
which stated that ondansetron could be effective in decreasing vomiting and limiting
hospital admission [5]. This was endorsed by the AAP in 2004 and although the recommendations do not support
the routine use of pharmacologic therapy, the policy states that, ondansetron may
be beneficial in limiting vomiting and hospital admissions [6]. Similarly, a European guideline stated that antiemetics might be of value in children
with severe vomiting [7].

Vomiting associated with acute gastroenteritis (AGE) is a distressing symptom, both
for children and their parents. Furthermore, vomiting limits the success of oral rehydration
in AGE leading to an increased use of intravenous (IV) rehydration, need for prolonged
emergency department stays and hospitalizations. Thus despite being a subject of controversy,
a number of antiemetic agents are now commonly administered worldwide in an attempt
to reduce vomiting in children with AGE. These include dopamine (D2) antagonists,
serotonin or 5-hydroxytryptamine (5-HT3) antagonists, anticholinergic agents, antihistamines,
benzodiazepines, and corticosteroids which are administered orally, intravenously
or rectally. Choosing between these therapeutic agents involves careful consideration
of a number of factors, including effectiveness, side effect profiles and cost. A
national survey conducted in United States of America (USA) estimates that 61% of
physicians would administer antiemetics during oral rehydration if they felt it to
be necessary [8]. Another survey carried out in Italy, reports that 79% of pediatricians use antiemetics
to control vomiting in AGE [9]. Antiemetics such as promethazine, prochlorperazine, and metoclopramide are known
to have serious side effects; hence they are less commonly prescribed [10]. Recently antiemetics such as ondansetron have been used in secondary care setting
in pediatric population. A number of randomized control trials have been carried out
to evaluate its efficacy, safety and cost effectiveness [11-18]. Some researchers have also used rectal dimenhydrinate [19] and dexamethasone [20] but the numbers of studies are limited and clear evidence of any effect on outcomes
is yet to be clear.

We conducted a systematic review followed by a meta-analysis to determine whether
antiemetic drug use in gastroenteritis provides symptomatic relief and improves other
clinically significant outcomes and whether important adverse effects result from
using these medications. We have reviewed the available literature and evaluated the
quality of included studies according to the Child Health Epidemiology Reference Group
(CHERG) adaptation of Grading of Recommendations, Assessments, Development and Education
(GRADE) criteria [21]. The review has been designed according to Lives Saved Tools (LiST) and is therefore
different from the previously done reviews.

Methods

We systematically reviewed all published literature until January 2012. A search was
conducted in Pubmed, Medline, Cochrane Libraries, EMBASE and World Health Organization
(WHO) regional databases to identify all published and unpublished clinical trials,
additional studies were identified through hand search of references from included
studies (figure 1). We used the Medical Subject Heading Terms (MeSH) and keyword-search strategy using
various combinations of: gastroenteritis, vomiting, antiemetics and children. No language
or date restrictions were employed in the electronic search. Two authors independently
assessed the eligibility using pre-defined inclusion and exclusion criteria and performed
data extraction. Any discrepancies between the reviewers in either the decision of
inclusion or exclusion of studies or in data extraction were resolved by discussion
aimed at reaching consensus.

Inclusion criteria

We limited the inclusion to randomized and quasi-randomized trials where any antiemetic
was administered to children with vomiting associated with AGE. We considered any
antiemetic administered orally, intravenously or as a suppository at any dosage, prescribed
to terminate or reduce vomiting versus a placebo or nothing. Our initial objective
was to evaluate the effectiveness of antiemetics in children aged 0 to 5 years presenting
with AGE. However, the literature search did not identify any studies that provided
us with data specific to this age group; hence we expanded our eligibility to include
studies which had recruited children aged 0 to 12 years. We excluded studies in which
patients had vomiting due to alternative etiologies, which were done on adults and
which did not have a placebo or a suitable control group.

Abstraction, analysis and summary measure

All the studies that met the final inclusion criteria were double data abstracted
into a standardized form for each outcome of interest. We extracted the following
details:

1. Study methods: method of allocation, masking of participants and outcomes, exclusion
of participants after randomization and proportion of losses to follow-up.

Each study was assessed and graded according to the CHERG adaptation of the GRADE
technique [21]. Individual studies were graded according to strengths and limitations of the study.
Studies received an initial score of high if a randomized or cluster randomized trial
and then the grade was decreased for each study design limitation, if applicable.
A study was downgraded if there were limitations in the conduct of studies e.g. inadequate
methods of sequence generation or allocation concealment and/or high loss to follow-up
(>20%). Risk of bias in the included studies was assessed according to the latest
Cochrane Handbook. A grade of “high”, “moderate”, “low” and “very low” was used for
grading the overall evidence indicating the strength of an effect on specific health
outcome [21].

Quantitative data synthesis

Outcomes were double data extracted and were analyzed using RevMan version 5.1. The
binary measure for individual studies and pooled statistics was reported as the relative
risk (RR) between the experimental and control groups with 95% confidence intervals
(CI). Mantel–Haenszel pooled RR and corresponding 95% CI were reported or the DerSimonian–Laird
pooled RR and corresponding 95% CI where there was an unexplained heterogeneity.

The weights given to each study were based on the inverse of the variance. Heterogeneity
was quantified by Chi2 and I2, which can be interpreted as the percentage of the total variation between studies
that is attributable to heterogeneity rather than to chance, a low p-value (less than
0.1) or a large chi-squared statistic relative to its degree of freedom and I2 values greater than 50% were taken as substantial and high heterogeneity. In situations
of high heterogeneity, causes were explored by sensitivity analysis and random effect
models were used.

Results

We identified 910 papers from the database search. After the initial title and abstract
screening, 20 full texts were reviewed to identify papers which met the inclusion
criteria and had outcomes of our interest. As no paper reported data exclusively for
the 0-5 years age group, we expanded our study population to include children up to
12 years of age. Seven papers [12,13,15,17-20] met our inclusion criteria and had the outcome measures of our interest, were finally
selected for abstraction and analysis (table 1). All of these were double blind randomized controlled trials that were conducted
in developed nations. Six of the seven studies were conducted in an emergency department
(ED) setup while one [19] was in an outpatient setup and was a multicenter study. Children analyzed by these
studies varied in age from 5 months to 12 years. Various drugs were used as antiemetics;
four trials used oral ondansetron, one used rectal dimenhydrinate, participants of
one trial were either given IV ondansetron or IV metoclopramide, and compared against
placebo, while participants of one trial were either given IV ondansetron or IV dexamethasone.
None of the studies had isolated the cause of AGE or stratified results according
to causative agents, although cases with dysentery were excluded from the trials.
To estimate the effectiveness of antiemetics and its possible role in gastroenteritis,
we found six papers that reported data on vomiting and hospitalization outcomes. Three
papers reported on outcomes of Intravenous fluid (IVF) requirements, oral rehydration
therapy (ORT) tolerance, IVF requirement rates and admission within 72 hours of discharge
from the ED. Table 2 shows the results and quality assessment of studies by outcome.

Vomiting

Data on vomiting available from six studies [12,13,15,17-19] and 830 participants was pooled and analyzed for this outcome. Results (Figure 2) indicate that antiemetics were associated with a significant 54% reduction in the
incidence of vomiting (RR: 0.46 95% CI: 0.35, 0.61). The follow up periods used for
this particular outcome varied across studies. As heterogeneity was high (Chi2 = 11.92, I2 = 50%, P = 0.06) a random effect model was used. Sub group analysis based on the
different antiemetics used, showed that oral ondansetron and rectal dimenhydrinate
were associated with a significant reduction of 65% (RR: 0.35, 95% CI: 0.26, 0.46)
and 40% (RR: 0.60, 95% CI: 0.44, 0.82) respectively while IV ondansetron and metoclopramide
had a non-significant reduction of 50% (RR: 0.50, 95% CI: 0.24, 1.04) and 20% (RR:
0.80, 95% CI: 0.50, 1.28) respectively although only one study was analyzed for all
the antiemetics except for oral ondansetron.

Figure 2. Forest Plot for the effect of antiemetics for the treatment of gastroenteritis on
incidence of vomiting

Hospitalization

Data from six studies [13,15,17-20] and 963 participants indicated that there was a significant 54% (RR: 0.46, 95% CI:
0.29, 0.74) reduction in the incidence of hospitalization after the use of antiemetics
(figure 3). As heterogeneity was low (Chi2 = 6.34, I2 = 5%, P=0.39) a fixed effect model was used. Subgroup analysis for different antiemetics
showed that oral and IV ondansetron significantly reduced the incidence of hospitalization
by 64% (RR: 0.36, 95% CI: 0.18, 0.72) and 79% (RR: 0.21, 95% CI: 0.05, 0.94) respectively.
While there was a non-significant reduction in the incidence of hospitalization of
23% (RR: 0.77, 95% CI: 0.21, 2.78) and 27% (RR: 0.73, 95% CI: 0.30, 1.79) when rectal
dimenhydrinate and IV dexamethasone were used as antiemetics respectively. Hospitalization
within 72 hours from discharge from the ED was also reported by three studies and
showed that oral ondansetron had a non-significant 34% (RR: 0.66, 95% CI: 0.37, 1.19)
reduction.

Figure 3. Forest Plot for the effect of antiemetics for the treatment of gastroenteritis on
hospitalizations during ED stay

Revisit rate

Four studies [13,15,17,18] evaluated the revisit rates with use of oral ondansetron with a total of 553 participants
and indicated that oral ondansetron reduced the revisit rates to the ED by a non-significant
3% (RR: 0.97, 95% CI:0.62, 1.53). There was no significant heterogeneity and hence a fixed effect model was used for
analysis.

IVF requirement rate

IVF requirement rate were analyzed in two ways by the studies included; first, if
the patient required IVF during the stay in ED and secondly if the patient required
IVF within 72 hours of discharge from the ED. Three studies [13,15,17] reported both the outcomes and evaluated the effect of oral ondansetron on IVF requirement
rates. Based on the analysis from the datasets of these three studies, oral ondansetron
reduced the IVF requirements during the ED stay by 60% (RR: 0.40, 95% CI: 0.29, 0.56)
and within 72 hours of discharge from ED by 34% (RR: 0.66, 95% CI: 0.37, 1.19). A
fixed effect model was used for analysis as there was low heterogeneity.

ORT tolerance rate

Tolerance to ORT as an outcome was reported by three studies [17,18,20] and it indicates a significant 22% (RR: 1.22, 95%CI: 1.01, 1.46) increase in tolerance
after the use of antiemetics. Subgroup analysis for different antiemetics shows that oral ondansetron is associated
with a 33% increase (RR: 1.33 95% CI: 0.98, 1.80), IV ondansetron with a 29% increase
(RR: 1.29 95% CI: 1.01, 1.63) and IV dexamethasone was associated with a non-significant
8% reduction (RR: 0.92, 95% CI: 0.67, 1.26) in ORT tolerance rates.

Recommendation for the LiST model

We applied the CHERG rules for evidence review to the outcomes assessed for the effect
of antiemetics on gastroenteritis in children. As there was no data on mortality;
either all-cause or cause specific, we used a severe morbidity outcome to estimate
the effect on mortality. The six RCTs reported a 54% decrease in hospitalization rates
for about 80 admissions. The results also report a 54% reduction in episodes of vomiting
after the use of antiemetics for 300 episodes of vomiting. As the studies included
did not isolate the specific cause of AGE and we cannot stratify our data according
to type of diarrhea thus these results are applicable to all cases of AGE, excluding
dysentery. Hence we estimate and propose a 54% reduction in diarrhea related mortality
with the use of antiemetics in cases of diarrhea associated with vomiting. (see Figure
4)

Figure 4. Application of standardized rules for choice of final outcome to estimate effect of
antiemetics in gastroenteritis

Discussion

Vomiting continues to be associated with hospitalization, use of IVF, and significant
morbidity among AGE affected children worldwide. Recently the role of antiemetics
for controlling vomiting in children has been debated. Clinical practice guidelines
for the treatment of children with gastroenteritis recommend supportive care using
ORT for mild to moderate dehydration, without fully endorsing the use of antiemetic
medications to control vomiting. However in clinical practice, it appears that antiemetics
are widely popular among physicians [8,22].

Our analysis of the effect of antiemetics in gastroenteritis suggests that antiemetics
are likely to be beneficial in children with vomiting. The RCTs included in our study
looked at ondansetron, metoclopramide, dimenhydrinate and dexamethasone. The administration
of oral ondansetron was found to reduce incidence of vomiting, reduction in hospitalization
and IVF requirements while IV ondansetron was associated with a significant increase
in tolerance to ORT. Rectal dimenhydrinate also significantly reduced the incidence
of vomiting but has only been evaluated by a single study. There is insufficient evidence
to support the role of IV metoclopramide in children with AGE as far as the incidence
of vomiting is concerned but significantly reduced the hospitalization rates. Rectal
dimenhydrinate also significantly reduced the incidence of vomiting and IV dexamethasone
did not significantly decrease hospitalization rates or increased tolerance to ORT.
The outcomes and recommendation from the meta-analysis are summarized in table 2 based on the LiST model suggested by the CHERG reviews of intervention effectiveness
on child survival [23].

Table 2. Quality assessment of trials of antiemetics on vomiting and hospitalization rates
in acute gastroenteritis

Oral ondansetron given as a single dose of 0.1-0.25 mg/kg [13,17] in the emergency department to children with mild to moderate dehydration decreases
the number of children with persistent vomiting. It also decreases the number of children
requiring IV rehydration and hospital admissions. Higher doses have also been used
but any added advantage is not apparent [15]. Oral ondansetron may be useful as an adjunctive measure to ORT in the outpatient
or primary care setting as well, although no study is available at the moment to confirm
this. Thus, it should be an important area of future research.

Adverse effects reported with use of ondansetron were limited to increased mean episodes
of diarrhea noticed in a few studies, although this was statistically non-significant.
A possible explanation could be the variable duration of follow-up periods employed
by different researchers, while it would be ideal for researchers to report the actual
output volume of stool rather than the number of episodes [24], which is usually impractical in outpatient clinical trials. The use of rectal dimenhydrinate
was not associated with increased episodes of diarrhea or any other major adverse
effects [19]. Other antiemetic medications such as metoclopramide appears to be less efficacious
in the treatment of gastroenteritis induced vomiting and are associated with more
adverse events than ondansetron.

The cost effectiveness of ondansetron has been another area of concern. However, an
economic analysis [14] in the USA, the administration of ondansetron to eligible children would prevent
approximately 29,246 IV insertions and 7,220 hospitalizations annually. It also reported
that at the current average wholesale price, its routine administration to eligible
children would annually save society US$65.6 million (US$49.1–US$81.1) and health
care payers US$ 61.1 million (US$46.2–US$76.3).

Currently, online pharmacies charge $20 to $30 per pill for the brand name Zofran
[25]. Although this seems expensive, if taken into the account the fact that use of single
dose of ondansetron reduces IVF requirements and admission rates, it may be extremely
cost effective. This might not be the case in developing countries where a majority
of children are treated at facilities that utilize minimal resources and cannot afford
expensive medications. Hence a very clear evidence of its efficacy and safety should
be available before it could be introduced as a standard of care in the clinical guidelines,
especially for both developing and underdeveloped countries.

The findings in this systematic review are to a large extent in agreement with those
reported by the Cochrane reviews [26] and previously done meta-analysis on the same subject [27-31]. Although we differ from the previously carried out reviews as we have only included
studies looking at children aged 0 to 12 years and we have evaluated the quality of
the studies and the outcomes based on the LiST model as suggested by CHERG intervention
review process. We have also based our recommendations on the CHERG intervention review
process [21].

A number of limitations can be observed from the included studies that extend to this
review. Firstly the use of antiemetics was studied in the ED setting only while the
role of oral antiemetics such as oral ondansetron in outpatient or primary care settings
is yet to be evaluated. Other study limitations include that a wide age range of participants
were included by different studies and there was no widely agreed-on definitions of
the outcome measures (e.g. incidence of vomiting, hospital admission, need for IV
rehydration) used by different studies and children were included with various degrees
of dehydration.

Currently we need more evidence on safety and efficacy of antiemetics in AGE. A study
currently underway will be assessing the use of ondansetron compared with domperidone
in children [32]. Studies also need to be done in primary care settings with evaluations of cost effectiveness
especially in developing countries. In the meantime, recommendations by the CDC focus
on appropriate fluid, electrolyte and nutritional therapy in all patients [5] and if vomiting continues with the possibility of IV rehydration, clinicians should
consider using oral ondansetron.

Conclusion

Antiemetics are effective for the management of gastroenteritis in children and have
the potential to decrease the morbidity and mortality burden due to diarrhea, when
introduced and scaled up.

Competing interests

Authors' contributions

Dr ZAB was responsible for designing the review and co-ordinating the review. JKD,
RK and RAS were responsible for: data collection, screening the search results, screening
retrieved papers against inclusion criteria, appraising quality of papers, abstracting
data from papers, entering data into RevMan, analysis and interpretation of data and
writing the review. ZAB and JKD critically reviewed and modified the manuscript in
addition to Stephen Freedman.

Acknowledgment

This work was supported in part by a grant from the Bill & Melinda Gates Foundation
(OPP1004060) to Evidence-based landscape analysis on Childhood Diarrheal disorders
and development of global consensus on priorities for research and interventions

Declarations

The publication costs for this supplement were funded by a grant from the Bill & Melinda
Gates Foundation to the US Fund for UNICEF (grant 43386 to "Promote evidence-based
decision making in designing maternal, neonatal, and child health interventions in
low- and middle-income countries”). The Supplement Editor is the principal investigator
and lead in the development of the Lives Saved Tool (LiST), supported by grant 43386.
He declares that he has no competing interests.

Roslund G, Hepps TS, McQuillen KK: The role of oral ondansetron in children with vomiting as a result of acute gastritis/gastroenteritis
who have failed oral rehydration therapy: a randomized controlled trial.